Viruses achieve latency by immune-suppressing mechanisms

The majority of people will be exposed to a virus in the Herpes family at some point that will remain in their body for the rest of their life.  The Herpes family is an example of viruses that can establish latency, which is when the virus remain dormant within the host cell and are no longer proliferating, but their viral genome is still present and is being replicated along with the host genome.  In their publication, Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4 T Cells, Mason et al. examined the mechanism of how these viruses establish latency.  The group focused on a member of the Herpes family, Human cytomegalovirus (HCMV).

HCMV infection is typically asymptomatic, unless the infected person has a compromised immune system.  During the initial infection, there is an extensive CD4+ and CD8+ T cell response (general information on T cells), which controls the active virus.  However, despite the initial immune response, the virus is unable to be cleared and it establishes latency within the host.  The virus establishing latency within the host is problematic because the virus is able to become active (lytic) again, and if this occurs at a time when the immune system is compromised, the individual will experience disease-like symptoms.  In order to clear these viruses from our body, it is important to understand how they are evading our immune system during latency. 

There are different proteins expressed at different stages of HCMV infection.  During the lytic (active) phase, one of the major viral proteins that are recognized by the T cells is gB which is considered one of the immediate early (IE) genes.  When IE genes are absent, this indicates that the virus is latent.  A small amount of HCMV viral genes are expressed during latency, namely UL138 and LUNA.  Interestingly, the viral genes expressed during latency are also expressed during lytic infection.  If there is a T cell response against UL138 and LUNA in both lytic and latent infections, why is it that the infection unable to be cleared in latency?

Infect Me With Parasites? TGIT(GFbeta)

The use of helminthic therapy (the intentional infection of a patient with parasitic worms) to treat autoimmune diseases has enjoyed recent popularity for treatment of conditions as diverse as Crohn’s disease (1) and multiple sclerosis (2) . The jury is still out on its efficacy, however, and the thought of intentionally infecting patients with parasites for therapeutic purposes seems counterintuitive if not downright crazy. Part of the controversy stems from the conflicting reports as to exactly how helminthic therapy works. Some researchers suggest that helminthic therapy works by an evasive maneuver on the part of the parasitic worms to trick the immune system into producing the wrong kind of response, a type 2 cytokine response. (3) The authors of a recent study used helminthic therapy in a mouse model of non-obese diabetes (an autoimmune disorder) in order to attempt an answer to this question, which will be the focus of this blog post. (4)

The authors first demonstrated, by immunostaining, that mice deficient in IL-4 (a immune signaling molecule critical to the development of a type 2 response) fail to develop a type 2 response when infected with a parasitic worm in contrast to control mice that had normal levels of IL-4 which then developed a type 2 response. Given the role of IL-4 in promoting a type 2 response, this result seems fairly obvious and unnecessary to report. This is vital piece of data, however for the next experiment that these scientists performed.

The scientists then measured the onset of diabetes in the mice they were experimenting upon (remember they are specially designed to be genetically pre-disposed to develop diabetes) by measuring glucose levels in their blood. Surprisingly, mice infected with the parasite, regardless of competency in producing IL-4, did not develop diabetes. This suggests that a shift to a type 2 response is not the critical factor in the protection afforded by helminthic therapy in this model. What then, one might ask, are those wriggly worms doing to fend off diabetes?

The scientists who authored this study thought that it might have to do with regulatory T cells at first, but flow cytometry experiments they performed showed no difference in the numbers of regulatory T cells in any condition, infected/uninfected or IL-4 competent or not. They then hypothesized that either IL-10 or TGFβ, which have been implicated in regulating diabetes in mice could play a role. (5) Further flow cytometry experiments showed that TGFβ production was the critical factor in infected mice that correlated with the resistance to diabetes.

The results of this study suggest that the protection against diabetes afforded by helminthic therapy is not a result of a shift to a type 2 cytokine response, nor by regulatory T cells, but by an increase in the production of TGFβ, which is an immune signaling molecule that serves to tamp down the immune response. This opens up questions as to whether or not infection with parasitic worms is actually needed in order to convey the same protection that administration of TGFβ may be able to provide. This alternative to helminthic therapy must be explored further.

References

1) Summers, R. W., Elliott, D. E., Urban, J. F., Thompson, R., & Weinstock, J. V. (2005). Trichuris suis therapy in Crohn’s disease. Gut, 54(1), 87-90.

2) Benzel, F., Erdur, H., Kohler, S., Frentsch, M., Thiel, A., Harms, L., Wandinger, K.-P., et al. (2011). Immune monitoring of Trichuris suis egg therapy in multiple sclerosis patients. Journal of helminthology, 1-9.

3) Hübner, M. P., Stocker, J. T., & Mitre, E. (2009). Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology, 127(4), 512-22.

4) Hubner, M. P., Shi, Y., Torrero, M. N., Mueller, E., Larson, D., Soloviova, K., Gondorf, F., et al. (2011). Helminth Protection against Autoimmune Diabetes in Nonobese Diabetic Mice Is Independent of a Type 2 Immune Shift and Requires TGF- . The Journal of Immunology.

5) Hancock, W. W., Polanski, M., Zhang, J., Blogg, N., & Weiner, H. L. (1995). Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. The American journal of pathology, 147(5), 1193-9.

Lack of Th17 Cell Generation in Patients with Severe Burn Injuries

Severe burn patients are immunodeficient and highly susceptible to infection of Candida albicans, a fungus that causes an opportunistic infection of the skin and mucosal membranes. Fungal infections can be attributed to 33% of mortality among patients with total body surface area (TBSA) burns. Above all, C.albicans infection results in the highest percentage of TBSA patient deaths [1].

Resistance against C.albicans infection is largely attributed to the anti-fungal activities of IL-17 producing CD4 T cells, or Th17 cells. Upon activation, CD4 T cells differentiate into three subsets of T helper cells; Th1, Th2, and Th17. Each type of Th cell produces a unique collection of cytokines, or chemical messengers, which activate different varieties of immune responses [2]. Th17 cells predominantly secrete IL-17, which is essential for mediating host defenses in mucosal surfaces such as the lungs and gut. Past research has implicated IL-17 in the regulation of neutrophils, which are leukocytes involved in the rapid responses of the innate immunity [3]. Specifically, IL-17 recruits neutrophils to a site of infection and enhances the function of epithelial cells, endothelial cells, and macrophages to produces pro-inflammatory cytokines [1]. Previous research implicates IL-17 deficiency in C.albicans infection and chronic mucocutaneous candidasis and demonstrates the necessity of IL-17 to combat fungal infections.

In the present study Inatsu and colleagues attempt to generate Th17 cell cultures in the presence of severely burned patient PBMC (peripheral blood mononuclear cells). PBMC are blood cells with a round nucleus such as monocytes and macrophages [4]. Prior to culture, patient’s PBMC were stimulated by C.albicans antigen (CAg), a protein derived from the fungus that can bind to a cell surface receptor and result in lymphocyte activation. The rationale was that CAg activated cells will be stimulated to produce Th17 cells and IL-17. Ultimately, Th17 were not detected in the cell cultures of CAg activated PBMC. Inatsu and colleagues hypothesis that IL-10, a cytokine detected in the sample of burn patient PBMC, inhibits the generation of Th17 cells and contributes to the increased susceptibility of TBSA individuals to C.albicans.